Many diseases do not affect the whole organism at the same time, but are restricted to particular kinds of tissue and are frequently restricted to certain limited areas of tissue or to certain parts of organs. Examples can be found in tumorous diseases, joint diseases and vascular diseases, and in particular with solid tumours and arterial vascular diseases.
Pharmacotherapy of these diseases generally takes place by the oral or intravenous administration of pharmaceutical substances which distribute themselves throughout the whole body and in many cases can cause undesirable effects in healthy tissue and in healthy organs, particularly with severe illnesses. These undesirable effects can limit the therapeutic applications. Selective treatment of the diseased tissue is achieved by means of specific pharmaceutical substances which bind to the diseased tissue (e.g. antibodies) during the chosen method of application or by selective administration e.g. by direct application to the diseased tissue, or by being supplied by a catheter in the blood vessel that is affected. In cases of selective administration there are problems which arise because of the mainly short duration of the effects of the pharmaceutical substances and because of the invasive methods of application, since any repeated administration is out of the question.
Problems for pharmacotherapy are caused by the special method of application and the necessity of achieving a significant prophylactic or therapeutic effect in one single application. In the past 10 years significant success has been achieved particularly in the treatment of arteriosclerotic vascular changes. Such changes frequently occur in localised areas. They lead to constrictions or occlusions of specific sections of the blood vessels which impair or prevent the supply of blood to the tissue which lies on the other side of the blockage. This mainly affects the heart, the legs, the brain, the kidneys and surgically altered vessels such as dialysis shunts. Narrowing of these vessels can be treated with a catheter which is introduced percutaneously and which can be introduced into the relevant blood vessels without causing a large amount of injury because of its small diameter. They mostly contain a balloon in the distal part which is folded around the catheter shaft and which can be expanded by means of a fluid. When it is still folded this balloon is pushed into the restricted part of the blood vessel where it is expanded for a short time (ranging from a few seconds to a few minutes) so that the original vessel lumen is restored and the blood can again pass through the originally constricted area.
At the same time a tubular piece of metal mesh (vessel support, stent) can be introduced to support the opened vessel lumen. This can be either mounted on the folded balloon or it can be released as an elastic, self-expanding stent by means of a special catheter.
While the initial success rate is over 90%—measured by the widening of the vessel lumen to approaching the size before the constriction appeared—with many patients a renewed constriction can occur several months after treatment (restenosis). The most significant cause is from the excessive proliferation of cells in the vascular wall triggered by injuries caused during the violent expansion of the vessel. This affects the smooth muscle cells in particular, which do not come to a standstill after the healing of the original injury. This process could be almost completely suppressed in the coronary arteries by coating the stent with antiproliferative pharmaceutical products. A requirement is that the pharmaceutical product is released slowly (i.e. over days and weeks) from a polymer matrix. The disadvantage of coating the stent is that healing is inhibited from taking place. Thrombi can form on the struts of the stent as long as they are in direct contact with the blood. Thrombi can lead to a sudden and total vascular occlusion, to infarction and to death. The struts must therefore become rapidly and permanently overgrown by an endothelial layer. This is inhibited by the sustained release of an active substance that inhibits cell proliferation.
There are no controlled studies available for peripheral arteries which demonstrate effective prophylaxis of restenosis by coating stents with pharmaceutical products. Certain self-expanding nitinol stents do however appear to reduce the restenosis rate to some extent without a coating of a pharmaceutical product being necessary (Schillinger M, Sabeti S, Loewe C et al. Balloon angioplasty versus implantation of nitinol stents in the superficial femoral artery N Engl J Med 2006; 354: 1879-88).
The coating of balloons is described in principle in EP 1 372 737 A. The active substance is applied by, for example, immersing the balloon in a solution of the active substance. In WO 2004/028582 A the possibilities of coating balloons in various stages of folding are described including when the balloons are preformed.
Constricted arteries, often connected with solid calcification, can mainly be expanded to their original lumen only by using a high pressure (8 to 20 atmospheres). This is achieved by using pressure resistant balloons whose diameter does not significantly change with increasing internal pressure.
The balloon forms a rigid cylinder which lies against the vascular wall as long as the diameter of the vascular lumen before the expansion of the balloon is smaller than the diameter of the balloon. With a suitably high pressure an active substance applied to the outside of the balloon is pressed against the expanded vascular wall.
Localised treatment using pharmaceutical substances may also be necessary without stretching the vascular lumen. Examples are the treatment of arteries following the removal of plaque material with mechanical (e.g. atherectomy catheters), thermal processes (e.g. lasers) or the treatment of changes to the vascular wall which do not lead to flow inhibiting stenoses (e.g. vulnerable plaques, overlying thrombi). Any overstretching and damage to the vessel is undesirable in such cases. If the customary angioplasty balloons are selected with a diameter which does not lead to any stretching of the vessel then their membrane only comes into contact with the irregularly shaped vascular wall in a few places and only transfers the pharmaceutical substance in those places.